1) The major scientific goal of this project is to determine the pathogenic mechanisms responsible for sepsis-induced acute lung injury (ALI), a leading clinical cause of the acute respiratory distress syndrome (ARDS). Laboratory investigation will be conducted in vivo to elucidate basic immunologic and inflammatory mechanisms of sepsis-related lung injury, including the role of mechanical ventilation in this process. The research program will place special emphasis on the roles of apoptosis, especially those mediated by Fas (CD95), and MyD88-dependent in ALl pathogenesis. 2) The major specific aims are: 1) to determine whether mechanical ventilation interacts with sepsis in vivo to synergistically induce ALI; 2) to determine if sepsis and mechanical ventilation promote pro-apoptotic responses in the lung that contribute to ALI; 3) to determine whether mechanical ventilation synergizes with sepsis to induce ALI via potentiation of MyD88-dependent pro-inflammatory mechanisms. 3) Experimental approach: Murine models of sepsis will be employed to address the specific aims. The relative roles of the Fas apoptotic and the MyD88-dependent pro-inflammatory will be assessed in experiments with lpr (Fas-deficient) and MyD88 -/- mice, respectively. 4) Expected results/significance: Sepsis alone is not expected to cause significant ALl but is anticipated to prime the lung for tissue injury in response to mechanical ventilation. Sepsis-induced/ventilator-associated ALI is expected to involve apoptosis of the lung epithelium and MyD88-dependent pro-inflammatory responses. The experimental approach is unique in that it utilizes a murine model of extra-pulmonary sepsis to study the pathogenesis of ALI and the modulating effects of concomitant mechanical ventilation. Results are expected to yield fundamental insights into the basic pathogenic mechanisms of sepsis-induced ALI and provide the basis for development of novel anti-apoptotic and anti-inflammatory therapeutic strategies for ALI/ARDS.